ES2897981T3 - Two component composition comprising acetylsalicylic acid - Google Patents

Abstract

A two-component composition for use in the treatment of impending myocardial infarction, wherein the two-component composition comprises a first and a second component, wherein said first component comprises 100-600 mg of acetylsalicylic acid (ASA) and optionally one or more pharmaceutically acceptable excipients; and wherein said second component comprises an aqueous solution comprising at least one pharmaceutically acceptable salt of an organic acid and optionally one or more pharmaceutically acceptable excipients, wherein the organic acid is selected from the group consisting of acetic acid, lactic acid, citric acid, ascorbic acid, malonic acid, succinic acid, glutaric acid and a combination thereof; and wherein the pH of the aqueous solution of the second component is 8-11.5; and wherein the pH of the solution obtained after adding and dissolving the ASA in the aqueous solution is in the range of 5-8.

Description

DESCRIPTION

Two component composition comprising acetylsalicylic acid

The present invention relates to a two-component composition for use in the treatment of impending myocardial infarction, wherein the two-component composition comprises a first and a second component, wherein said first component comprises 100-600 mg of acetylsalicylic acid (ASA) and optionally one or more pharmaceutically acceptable excipients; and wherein said second component comprises an aqueous solution comprising at least one pharmaceutically acceptable salt of an organic acid and optionally one or more pharmaceutically acceptable excipients, wherein the organic acid is selected from the group consisting of acetic acid, lactic acid, citric acid, ascorbic acid, malonic acid, succinic acid, glutaric acid and a combination thereof; and wherein the pH of the aqueous solution of the second component is 8-11.5; and wherein the pH of the solution obtained after adding and dissolving the ASA in the aqueous solution is in the range of 5-8. The present invention further relates to a capsule for use in the treatment of impending myocardial infarction comprising a first and a second chamber, wherein the first chamber comprises 100-600 mg of acetylsalicylic acid and optionally one or more pharmaceutically acceptable excipients. ; and wherein said second chamber comprises an aqueous solution comprising at least one pharmaceutically acceptable salt of an organic acid and optionally one or more pharmaceutically acceptable excipients, wherein the salt of an organic acid is selected from the group consisting of a salt of acetic acid, a salt of citric acid, a salt of ascorbic acid, and a combination thereof; and wherein the pH of the aqueous solution in the second chamber is 8-11.5; and wherein the pH of the solution obtained after adding and dissolving the ASA in the aqueous solution should be in the range of 5-8. The two-component composition allows immediate dissolution of ASA by mixing the first and second components of the present two-component composition, and is useful in the treatment of impending myocardial infarction. The present two-component composition is particularly useful as a first aid treatment in patients who need immediate administration of ASA to prevent the development of a heart attack, or to reduce the extent of damage from a heart attack.

Background of the invention

Cardiovascular diseases are one of the main causes of mortality and morbidity in the Western world. According to the World Health Organization, cardiovascular disease is the leading cause of death globally, and an estimated 17.5 million people die each year from cardiovascular disease, which is estimated at approximately 31% of all deaths worldwide. Furthermore, 80% of all cardiovascular disease deaths are caused by heart attacks or strokes (cf.

http://www.who.int/cardiovascular diseases/en/ and

http://www.who.int/mediacentre/factsheets/fs317/en/).

Although numerous medicinal agents are available for the treatment of various cardiovascular diseases, such as, for example, cholesterol-lowering drugs, numerous drugs aimed at lowering blood pressure, anticoagulants, etc., patients with cardiovascular diseases still have a high risk of premature death.

A myocardial infarction (heart attack) is usually announced by precursors, that is, warning signs that occur in advance, which allows action and thus avoid or reduce the serious consequences of a myocardial infarction.

It is well known that the probability of survival of patients experiencing symptoms of a myocardial infarction is significantly increased if the patients receive ASA as quickly as possible, preferably immediately. Therefore, rapid administration of ASA is crucial to prevent death and reduce damage to the cardiovascular system. To ensure rapid absorption and high bioavailability, ASA must be dissolved at the time of administration. However, ASA has poor solubility, which makes it difficult to rapidly provide an aqueous solution of ASA. In addition, ASA and ASA salts hydrolyze rapidly in water (Connors et al., Chemical stability of Pharmaceuticals, A Handbook for Pharmacists, pages 151-160), so it is hardly possible to store dissolved ASA.

Therefore, to successfully treat an upcoming myocardial infarction, a patient needs to have ASA available in a form that can be rapidly and easily dissolved and rapidly taken or administered to the patient.

Today, ASA-containing effervescent tablets are commonly used as an immediate treatment for patients experiencing symptoms of a heart attack. A product commonly used for this purpose is, for example, Dispril®, an effervescent tablet containing 300 mg of acetylsalicylic acid.

Effervescent formulations in general, as well as those containing ASA, commonly comprise effervescent agents, such as an acid source together with a type of carbonate or hydrogen carbonate, such as sodium hydrogen carbonate or calcium carbonate.

Before administration of the effervescent tablets, the tablets should be dissolved in water or dissolved in saliva in the patient's mouth. This may take several minutes, typically 5 minutes.

GB2321231 discloses a two component product for the treatment of impending heart attack including a first compartment containing 30 ml of water and a second compartment containing 300 mg ASA in dissolvable tablet form. Before administration, the two components are mixed, the ASA rapidly dissolves, and the resulting solution is administered orally to the patient.

WO2015/061521 describes an effervescent tablet comprising high levels of ASA and an alkaline substance (eg sodium hydrogen carbonate) and vitamin C.

Document EP1428525 describes a pharmaceutical preparation for veterinary use containing ASA in buffered powder form. Said powder still needs water to dissolve, and therefore will not solve the problem by needing a glass of water available.

US20120316140 A1 describes a soluble aspirin composition (=ASA), wherein the soluble aspirin composition (ASA) when introduced into water undergoes a reaction. This reaction triggers an effervescent action and disintegration of the As granules to quickly dissolve in the water.

US5776431 A discloses water soluble aspirin compositions comprising aspirin, potassium citrate (tri) monohydrate or sodium citrate (tri) dihydrate and a surface active agent (eg sodium lauryl sulfate). Such a composition comprising 500 mg of aspirin is dissolved in 150 ml of water.

Multi-compartment capsules comprising different chambers for ingredients with different physical states have been described in documents US2005008690 A1 and EP2777802 A1. However, said document does not describe a successful incorporation of ASA in said capsule.

The drawbacks with prior art tablets are that patients need a glass of water to dissolve the tablets and complete dissolution can take some time, often too long. Additionally, a patient experiencing signs of an impending (ie developing) myocardial infarction typically has reduced or deficient saliva production, resulting in a dry mouth. Reduced or deficient saliva production makes it difficult to dissolve an ASA-containing oral tablet. Therefore, it is crucial that the patient has fluid available to dissolve and/or ingest the ASA.

In addition, ASA-containing chewable tablets are available as immediate treatment for patients experiencing symptoms of a heart attack. However, for the same reason as mentioned above, also the dissolution and release of ASA from a chewable tablet is often hampered by reduced or deficient production of salvia in patients.

On the whole, although ASA-containing products are available for emergency use (see, for example, http://dummypage2.tripod.com/index.htm#origin), such products will be unsuitable in the absence of water or production of poor saliva.

Therefore, there is still a need for an ASA formulation or system suitable for rapidly providing an ASA-comprising aqueous solution that can be administered to patients in need of urgent treatment of impending myocardial infarction. In particular, there is a need for an ASA formulation that avoids the need for additional water or adequate saliva production in a given patient for the ASA to be rapidly administered and absorbed.

Summary of the invention

The present inventor has discovered that a stable formulation of ASA can be provided with a two-component system comprising the active ingredient ASA in a first compartment and an aqueous solution of an organic acid salt in a second compartment, which on mixing the The contents of the two compartments quickly provide an aqueous solution of ASA that can be administered or ingested by a patient in need.

In particular, the present invention relates to a two-component composition for use in the treatment of impending myocardial infarction, wherein the two-component composition comprises a first and a second component, said first component comprising 100- 600 mg of acetylsalicylic acid and optionally one or more pharmaceutically acceptable excipients; and wherein said second component comprises an aqueous solution comprising at least one pharmaceutically acceptable salt of an organic acid and optionally one or more pharmaceutically acceptable excipients, wherein the organic acid is selected from the group consisting of acetic acid, lactic acid, citric acid, ascorbic acid, malonic acid, succinic acid, glutaric acid and one of its combinations; and wherein the pH of the aqueous solution of the second component is 8-11.5; and wherein the pH of the solution obtained after adding and dissolving the ASA in the aqueous solution is in the range of 5-8. Said pharmaceutically acceptable excipient of the second component could be a carbonate, such as for example sodium carbonate, such as for example sodium carbonate anhydride.

According to one aspect, the organic acid salt is selected from the group consisting of an organic acid alkali metal salt, an organic acid alkaline earth metal salt, and a combination thereof. According to yet another aspect, the organic acid salt present in the second component of the present two-component system is selected from the group consisting of an organic acid sodium salt, an organic acid potassium salt, and a combination thereof.

In yet another aspect, the second component of the aqueous solution comprises a salt of citric acid, such as sodium or potassium citrate.

According to one aspect, the second component of the aqueous solution comprises a salt of a citric acid, such as sodium citrate dihydrate.

In yet another aspect, the second composition of the two component composition has a pH of about 8.

In yet another aspect, the second composition of the two component composition has a pH of about 11.5.

In yet another aspect, the second composition of the two-component composition of the invention comprises a preservative. In one aspect, the preservative is a paraben or benzalkonium chloride.

In one aspect of the present invention, the preservative is selected from the group consisting of methyl paraben, ethyl paraben, propyl paraben, and benzalkonium chloride.

In one aspect of the present invention, the preservative is selected from the group consisting of methyl paraben salt, ethyl paraben salt, propyl paraben salt, and benzalkonium chloride.

In yet another aspect, the second composition comprises, in addition to the salt of an organic acid, a salt of a paraben, such as a sodium salt of a paraben.

In yet another aspect, the paraben is selected from the group consisting of sodium methyl paraben and sodium propyl paraben.

According to yet another aspect of the invention, the volume of the aqueous solution of the second component is in the range of 6 ml - 50 ml. According to one aspect, the volume of the second component is in the range of 10-15 ml.

In one aspect, the two component composition according to the invention comprises 300-325mg ASA in the first component and wherein the volume of the second component is in the range 8-15ml.

According to another aspect, there is provided a two-component composition comprising a) a first component consisting of 300-325 mg of ASA, and b) a second component comprising 10-15 ml of an aqueous solution consisting of 30- 50 mg/mL Sodium Citrate and a preservative selected from the group consisting of Sodium Methyl Paraben, Sodium Ethyl Paraben, Sodium Propyl Paraben, and Benzalkonium Chloride.

According to one aspect, the first component comprising the ASA is dissolved in the second component comprising the organic acid salt, thereby providing a ready-to-use aqueous solution of aspirin prior to administration.

According to yet another aspect of the invention, said ready-to-use aqueous ASA solution is obtained within about 2 minutes. In yet another aspect, said ready-to-use aqueous ASA solution is obtained within about one minute or less. In yet another aspect, said ready-to-use aqueous ASA solution is obtained within 0.5-1 minute. According to yet another aspect, said ready-to-use aqueous ASA solution is obtained within about 10-40 s. According to yet another aspect, said ready-to-use aqueous ASA solution is obtained within about 15-20 s.

Furthermore, the present invention provides a capsule for use in the treatment of impending myocardial infarction comprising a first and a second chamber, wherein the first chamber comprises 100-600 mg of aspirin and optionally one or more pharmaceutically acceptable excipients; and wherein said second chamber comprises an aqueous solution comprising at least one pharmaceutically acceptable salt of an organic acid and optionally one or more pharmaceutically acceptable excipients, wherein the salt of an organic acid is selected from the group consisting of an acetic acid salt, a citric acid salt, an ascorbic acid salt, and a combination thereof; and wherein the pH of the aqueous solution in the second chamber is 8-11.5; and wherein the pH of the solution obtained after adding and dissolving the ASA in the aqueous solution should be in the range of 5-8. Said pharmaceutically acceptable excipient of the second component could be a carbonate, such as, for example, sodium carbonate, such as sodium carbonate anhydride.

In another aspect, the second chamber comprises an aqueous solution of a salt of citric acid, such as sodium citrate or sodium citrate dihydrate.

In another aspect, the second chamber of the capsule comprises an aqueous solution of an organic acid salt having a pH of about 8.

In yet another aspect, the second chamber of the capsule comprises an aqueous solution of an organic acid salt having a pH of about 11.5.

In yet another aspect, the second chamber of the capsule further comprises a carbonate, such as, for example, sodium carbonate, such as, for example, sodium carbonate anhydride.

In yet another aspect, the aqueous solution in the second chamber of the capsule further comprises a preservative, such as a paraben, such as a salt of a paraben, such as a sodium salt of a paraben. The second chamber may also comprise benzalkonium chloride as a preservative.

In one aspect, said paraben is selected from the group consisting of sodium methyl paraben and sodium propyl paraben.

Finally, the present invention provides a composition or capsule for use in a method of treating impending myocardial infarction by administering an aqueous solution of ASA to a patient in need thereof, said method comprising the steps of:

a) providing a two-component composition or capsule comprising a first and a second component/chamber according to the present invention;

b) mixing the composition of the first component/chamber comprising a pharmaceutically acceptable amount of ASA with the composition of the second component/chamber comprising an aqueous solution of a salt of an organic acid comprised in the second chamber, to thus obtain an aqueous solution from ASA;

c) administer to those who need it the mixture obtained in step b).

According to one aspect, the aqueous ASA solution obtained in step b) is provided within about two minutes or less, such as about one minute or less.

According to another aspect of the present invention, an aqueous solution of ASA is obtained within 15-20 seconds.

Definitions

The term "cardiovascular disease" as used in the present description refers to diseases in which patients suffering from cardiovascular disease are at risk of having a heart attack. In particular, "cardiovascular diseases" as used in the present description include ischemic heart disease, congestive heart failure, hypertension, valvular heart disease, general atherosclerosis, hypercholesterolemia, etc. The disease spectrum of ischemic heart disease includes stable and unstable angina and acute myocardial infarction, conditions generally treated pharmacologically or by coronary revascularization. Revascularization procedures can be performed with a catheter or through a coronary artery bypass graft.

The product of the present invention is applicable in the treatment of impending acute myocardial infarction, where the terms "myocardial infarction" and "heart attack" are used interchangeably in the present description.

The terms "treating" or "treating" as used herein refer to reducing the severity and/or elimination of symptoms, preventing the (further) development of a heart attack, and ameliorating or lessening the damage that can be caused by a heart attack.

Patients diagnosed with any of the indications listed above may be at risk of developing a heart attack or experiencing symptoms or warnings that a heart attack is imminent. The terms "treatment", "treating" or "treating" as used herein in accordance with the present invention refer to the treatment of patients diagnosed with cardiovascular disease as defined above, and in need of ASA due to the occurrence of an imminent acute myocardial infarction.

The terms "aspirin" or "acetylsalicylic acid" or "ASA" are used interchangeably in the present description.

The term "component" as used in the present description with respect to the first and second components of the present two-component composition refers in the present description to a component that comprises at least one ingredient or compound, and that can also be a mixture of different ingredients or compounds.

The term "two-component composition" as used herein refers to a product comprising at least two compositions that are kept separate prior to administration, and that must be mixed to provide a ready-to-use solution that it is given to patients who need it.

The term "pH-regulating agent" or "acidity-regulating agents" as used herein refers to a compound added to the first or second component of the present composition to change or maintain the pH of the composition.

The term "preservative", as used in the present description, refers to a substance or chemical commonly added to the pharmaceutical composition to prevent microbial growth or decomposition or unwanted chemical changes in a product.

The term "sweetening agent" as used in the present description refers to compounds commonly added to the pharmaceutical composition to sweeten or mask an unpleasant taste caused by the active ingredient or any of the excipients used in the composition.

The term "flavoring agent" as used in the present description refers to compounds commonly added to the pharmaceutical composition to provide a pleasant taste and/or mask an unpleasant taste caused by the active ingredient or any of the excipients used in the composition.

Detailed description of the invention

For patients experiencing a heart attack or experiencing symptoms or warnings that a heart attack is imminent, administration of As a taken as soon as possible is shown to increase the chances of survival and reduce the risks of developing damage to the cardiovascular system. and in the heart. The appropriate dose of ASA for such use is found to be 300 mg, which corresponds to the amount of active ingredient in the Dispril® effervescent tablet, cf. Elwood et al., 2001, The Pharmaceutical Journal, 266:315. Dispril® tablets comprise calcium carbonate, corn starch, citric acid, talc, saccharin and sodium lauryl sulfate (http://slv.no/layouts/Preparatomtaler/Spc/0000-02602.pdf).

The problem with prior art standard tablets containing ASA, such as Dispril®, is that they must first be dissolved in water and therefore a glass of water must be available whenever necessary. In addition, the lack of saliva in the mouth in patients suffering from an imminent heart attack, due to acute fear and adrenergic reactions, makes it difficult for patients to dissolve the tablets in the mouth. In both scenarios, this results in the need for water, which is inconvenient for quick administration. Furthermore, the time required to dissolve prior art tablets results in the fact that patients requiring immediate administration of ASA do not receive said medication quickly enough.

The present invention solves this problem by providing a product that ensures rapid dissolution of ASA and provides a solution that can be quickly administered to the patient, regardless of whether or not a glass of water is available and independent of the patient's saliva production.

Acetylsalicylic acid (ASA) is commonly known as aspirin and has the following structure:

The ASA is assigned the CAS registry number 50-78-2. Aspirin is used in the treatment of numerous conditions, for example, as an analgesic, in the treatment of inflammatory disorders, cardiovascular disorders, etc. In particular, it is used to reduce the risk of death from heart attack. However, ASA has poor water solubility, and ASA's low solubility makes it difficult to rapidly provide a solution to administer when patients are at immediate risk of heart attack. In standard pharmaceutical compositions, ASA rearranges into a soluble salt upon dissolution of the composition to improve solubility. Both ASA and ASA salt are unstable in aqueous solutions and rapidly hydrolyze to form acid. salicylic and acetic acid (Connors et al., Chemical of Pharmaceutical, A Handbook for Pharmaceutis, pages 151-160).

The present invention provides a two-component composition for use in the treatment of impending myocardial infarction, wherein the two-component composition comprises a first and a second component, said first component comprising 100-600 mg of acetylsalicylic acid (ASA) and optionally one or more pharmaceutically acceptable excipients; and wherein said second component comprises an aqueous solution comprising at least one pharmaceutically acceptable salt of an organic acid and optionally one or more pharmaceutically acceptable excipients, wherein the organic acid is selected from the group consisting of acetic acid, lactic acid, citric acid, ascorbic acid, malonic acid, succinic acid, glutaric acid and a combination thereof; and wherein the pH of the aqueous solution of the second component is 8-11.5; and wherein the pH of the solution obtained after adding and dissolving the ASA in the aqueous solution is in the range of 5-8. For example, the second component may comprise an effervescent agent, such as a carbonate. Typically, carbonates commonly used in effervescent tablets or powders, such as, for example, sodium carbonates or calcium carbonates, may be used in the second component of the present invention. According to one embodiment, a pharmaceutically acceptable excipient of the second component is a sodium carbonate, such as, for example, sodium carbonate anhydride.

The two-component composition according to the present invention represents an improvement in the emergency treatment of patients who have an imminent heart attack, or who are in the process of developing a heart attack, since it provides:

- an out-of-the-box solution comprising ASA,

- Immediate treatment of impending myocardial infarction without the need for a glass of water,

- Immediate treatment of myocardial infarction independent of saliva production in a given patient,

- a ready-to-use emergency medical product that can be easily carried by a wide population, including patients at risk of developing a heart attack, as well as their families, or is available in first aid kits in private homes or places as well as in emergency rooms at doctors' offices and hospitals.

In accordance with the present invention, the ASA present in the first composition dissolves rapidly when mixed with or added to the aqueous solution comprised in the second composition/compartment.

The salt of an organic acid as used in accordance with the present invention should provide for the formation of a readily soluble acetylsalicylate, such as sodium acetylsalicylate or potassium acetylsalicylate. The aqueous solution of the organic acid salt must have sufficient buffering capacity to slow or counteract the reduction in pH affected by mixing with ASA. According to one aspect, the pH of the aqueous solution of the second component of the present invention has a pH of about 8-9, such as 8-8.5. In yet another aspect, the second composition of the two component composition has a pH of about 11.5.

Without wishing to be bound by theory, it is believed that the ASA comprised in the first component when mixed with the second component ionizes contributing to the rapid delivery of a solution of the ASA.

In order to avoid hydrolysis of ASA, the pH of the solution obtained after adding and dissolving ASA in the aqueous solution should be in the range of 5-8. According to one aspect, the pH of the solution obtained by mixing the first and second components of the present invention is about 5.2.

In yet another aspect, the solution obtained by mixing the first and second components provides an ASA solution having a pH in the range of 6.6 - 7.6, such as in the range of 6.9 - 7.3 . According to one aspect, the pH of the solution obtained by mixing the first and second components of the present invention is about 7.1.

The desired pH of the aqueous solution of the second component can be further obtained by including a suitable pH adjusting agent.

According to one embodiment, a citric acid salt is used in the second component, such as sodium citrate. According to another embodiment, the citric acid salt used in the second component is sodium citrate dihydrate (trisodium citrate). The use of a citric acid salt as the organic acid is furthermore advantageous since the citric acid also provides a pleasant taste. Therefore, if, for example, citric acid sodium salt is used as the organic acid in the second component, it is not necessary to add more flavoring agents.

Another aspect of the present invention is that the ASA solution does not require the use of a surfactant. According to one aspect of the present invention, the second component of the present two-component system comprises an aqueous solution, comprising at least one pharmaceutically acceptable salt of an organic acid as defined in the claims, and optionally one or more pharmaceutically acceptable excipients. acceptable, provided that one or more pharmaceutically acceptable excipients is not a surfactant. Said pharmaceutically acceptable excipients of the second component could be a carbonate, such as for example sodium carbonate, such as for example sodium carbonate anhydride. To preserve the aqueous solution comprised in the second composition/compartment of the two-component composition according to the present invention, one or more preservatives are added to the aqueous solution.

Any pharmaceutically acceptable preservative that is effective as a preservative at a pH of about 8 may be used. According to one embodiment, parabens are used as a preservative in the second component of the present two-component composition.

Parabens (hydroxybenzoates) are a class of preservatives commonly used in pharmaceutical compositions. Parabens are used, among other things, to prevent the growth of microorganisms and are active against a wide spectrum of microorganisms. According to one aspect of the invention, parabens applicable as preservatives according to the present invention may be selected from the group consisting of methyl paraben, ethyl paraben and propyl paraben.

Alternative preservatives other than parabens suitable for use in a two-component composition according to the present invention are preservatives that are effective as preservatives at a pH in the range of 4-10. A non-limiting example of an alternative preservative that can be used is benzalkonium chloride.

Some parabens may be poorly soluble in water. In order to provide a more convenient and efficient manufacturing process for the preparation of the aqueous solution of the second component of the present invention, an alkaline salt of a paraben can be used. A sodium salt of a paraben is particularly applicable.

According to one aspect, methyl paraben sodium salt (Nipagin M sodium™) or propyl paraben sodium salt (Nipasol M sodium™) is used as a preservative in the aqueous solution of the second component of the present composition.

The pH of an aqueous solution of a sodium salt of a paraben will produce a basic solution with a pH of about 9. In the presence of a salt of an organic acid, such as citric acid, the pH can be even higher. In that case, the pH can be lowered by the addition of a pharmaceutically acceptable pH adjusting agent, such as by the addition of citric acid. In addition, other pharmaceutically acceptable pH adjusting agents can be used, such as, for example, acetic acid, lactic acid and/or ascorbic acid.

According to one aspect, the aqueous solution of the second component consists of an aqueous solution of sodium citrate, citric acid and at least one alkaline salt of a paraben, such as methyl paraben and/or propyl paraben.

According to the present invention, the first component comprises ASA in an amount of 100 mg to 600 mg. In order to treat or reduce damage to impending myocardial infarction, the first component of the present invention typically comprises 300 to 325 mg of ASA.

The volume of the aqueous solution of the second component of the present two-component composition depends on the specific medical indication as well as the size of the device separately comprising the two components of the composition. Typically, the volume of the second aqueous solution of the second component is within the range of 6-50 ml, such as 6-40 ml, such as 8-30 ml, such as 8-20 ml, or any number in or between said intervals. According to one embodiment of the present invention, the volume of the aqueous solution of the second component is in the range of 8-15 ml. According to one embodiment, the volume of the aqueous solution is in the range of 10-12 ml.

According to one embodiment, the first component comprises 100 to 600 mg of ASA, which will be dissolved in 6-50 ml of the aqueous solution of the second component of the present two-component composition.

According to another embodiment, the first component comprises 300 mg of ASA, and the second component comprises 8 to 15 ml of the aqueous solution.

According to yet another embodiment, the first component comprises 300 mg of ASA, and the second component comprises about 8 ml of the aqueous solution.

According to yet another embodiment, the first component comprises 300 mg of ASA, and the second component comprises about 10 ml of the aqueous solution.

According to yet another embodiment, the first component comprises 300 mg of ASA, and the second component comprises about 11 ml of the aqueous solution.

According to yet another embodiment, the first component comprises 300 mg of ASA, and the second component comprises about 12 ml of the aqueous solution.

According to yet another embodiment, the first component comprises 300 mg of ASA, and the second component comprises about 14 ml of the aqueous solution.

According to yet another embodiment, the first component comprises 300 mg of ASA, and the second component comprises about 15 ml of the aqueous solution.

According to one embodiment, the present invention provides two component compositions comprising a first and a second component, the first component 300-325 mg ASA; and the second component consisting of 10-15 ml of an aqueous solution consisting of 30-50 mg/ml of a citrate, such as sodium citrate, and 1 mg/ml of a paraben, such as methyl-p-hydroxybenzoate.

According to one aspect, there is provided a two component composition comprising a first component ASA in the range 300-325mg and a second component comprising an aqueous solution comprising 30-50mg/ml sodium citrate.

According to one aspect, there is provided a two-component composition comprising a first component of ASA in the range of 300-325 mg and a second component comprising an aqueous solution comprising about 150 mg/ml sodium citrate dihydrate.

According to yet another aspect, there is provided a two-component composition consisting of a) a first component comprising 300-325 mg ASA; and b) a second component comprising 10-15 ml of an aqueous solution comprising approximately 150 mg/ml sodium citrate dihydrate and a carbonate such as anhydrous sodium carbonate

According to another aspect, there is provided a two-component composition comprising a first component comprising 300 mg of ASA, and the second component comprising an aqueous solution comprising about 50 mg/ml of a citric acid salt.

The present first and/or second component of the present two component composition may optionally comprise other pharmaceutically acceptable excipients. For example, flavoring agents may be added to provide a pleasant taste and/or mask an unpleasant taste caused by the active ingredient or any of the excipients used in the composition. Non-limiting examples of compounds that can be used for the purpose of providing a certain flavor are citric acid, acetic acid and lactic acid, mint oil or fruit or berry juice, such as for example black currant juice.

According to one aspect, a flavoring agent is added to the second component of the present two-component composition. For example, peppermint oil may be added to the second component of the present composition, such as, for example, in amounts of about 1% (v/v) of the amount of the second component. Alternatively, blackcurrant oil may be added to the second component of the present composition, such as, for example, in the amount of 20% (v/v) of the amount of the second component. Black currant juice can also act as a pH regulating agent.

The present two-component composition may further include sweetening agents to enhance the flavor or mask the unpleasant taste of the other ingredients of the composition. The person skilled in the art is well known for the various sweetening agents commonly used as sweetening agents in pharmaceutical composition. A non-limiting example of a sweetening agent that can be used with respect to the present invention is sodium saccharin. Sodium saccharin may be added to the second component of the present composition, such as, for example, in amounts of about 0.03 to 0.06% (w/v) of the amount of the second component.

The two component composition included in the present invention can be administered to the patient in need by using a device or capsule comprising said first component and the second component in separate departments or chambers of a device or capsule. A predetermined amount of the first component and a predetermined amount of the second component, upon operation of the device or capsule, will immediately mix and form a ready-to-use solution of dissolved ASA to be taken or administered to a patient in need.

For example, a capsule for segregated storage of miscible two-component substances as described in WO00/66456 can be used in conjunction with the present invention for the treatment or prevention of myocardial infarction.

Packaging for keeping products separate before use as described in WO98/38104 can also be applied for the purposes of the present invention.

The person skilled in the art will understand that a device, package or capsule can be designed for the segregated storage of miscible substances of two components, such as a first component comprising a dry powder comprising ASA and a second component comprising a dissolution solution. according to the present invention, it can be designed in various ways. It should be understood that the two-component composition according to the present invention can be placed in any capsule, package or device that provides immediate dissolution of the ASA comprised in the composition of the first component when mixed with the dissolution solution of the composition of the second component. regardless of the exact design of the capsule, package or device in which the two components can be placed as long as the two components are separated during storage and before use.

The chamber volume of the capsule or storage device to be used with the present second component of the two-component composition is sized to store an aqueous solution that allows dissolution of the desired amount of ASA in accordance with the present invention. Similarly, the chamber volume of the capsule or storage device to be used with the present first component of the two-component composition of the present invention is sized to store the desired amount of said first component.

EXAMPLES

Example 1 Preparation of a two-component composition, dissolution of ASA in water with citric acid and a preservative

Test solutions not falling within the scope of the claims are reference examples. The following aqueous solutions (test solutions) were prepared by dissolving and mixing citric acid and a preservative in water. The amount of said ingredients is listed in table 1.

Table 1

Sample D was included in order to test the effect of the presence of the preservative on ASA dissolution, and to assess whether the presence of a preservative resulted in unwanted foaming.

A device as described in WO98/38104 provided by Bormioli Rocco S.p.A., Italy, was used in order to test the dissolution characteristics of test solutions.

8, 10, 12 and 14 ml of the test solutions A-D, respectively, were filled into the container (bottle) of the test device (3-phase kit with PET bottle, Bormioli Rocco S.p.A., Italy). Next, 300 mg of ASA was placed in the powder compartment of the device. The lid comprising the powder compartment and the cutting element was assembled with the container comprising the test solution.

The lid is then lowered until the cutting element breaks the seal that keeps the powder and solution separate. The severing of the seal resulted in the ASA contained in the powder compartment being released into the test solution in the container. The device was then shaken for about 0.5 to 1 minute or more in case all the ASA was not dissolved.

The following samples were tested:

Table 2 samples tested in two-component device

The results show that an aqueous solution of a citric acid salt can be used, also in the presence of methyl-p-hydroxybenzoate, to provide rapid dissolution of ASA. The results also show that sodium citrate must be in excess to obtain a pH in the final ASA solution that allows a rapid solution of ASA.

Should the pH obtained by mixing the ASA with the aqueous citric acid solution be too low, the ASA will not dissolve sufficiently within the time required to provide rapid administration of ASA to the patient. In particular, the results show that test solution C, which when mixed with 300 mg of ASA gave an aqueous solution of ASA with a pH of 5.2, showed better dissolution characteristics compared to, for example, solution test A, which, when mixed with 300 mg of ASA, gave a pH of 4.1 for the ASA solution obtained.

Furthermore, the results show that test solutions comprising 50 mg/ml sodium citrate resulted in faster dissolution of ASA compared to test solutions comprising 10 or 30 mg/ml sodium citrate, respectively. .

Finally, the results showed that a test solution volume of 10, 12 and 14 ml, respectively, dissolved ASA faster compared to 8 ml samples of the test solutions. In particular, samples 3C, 4B, 4C and 4D performed very well and provided sufficient dissolution of all ASA within 0.5-1 minute. The solution was visually inspected.

The results also showed that the preservative used did not affect the dissolution of ASA and did not result in any unwanted foaming.

Figure 1 shows an image of the device filled with samples 3C and 4C from Table 2.

Example 2 Preparation of a two component composition, dissolution of ASA in water with trisodium citrate and carbonate

The following aqueous solution (test solution) was prepared by dissolving and mixing sodium citrate dihydrate (trisodium citrate) and anhydrous sodium carbonate in water. The amount of said ingredients is listed in table 2.

Table 2

The device used in example 1 (described in WO98/38104 provided by Bormioli Rocco S.p.A., Italy) was used as described in example 1 for the testing of test solution E.

15 ml of test solution E was filled into the container (bottle) of the test device (3-phase kit with PET bottle, Bormioli Rocco S.p.A., Italy).

The pH of the aqueous solution of sodium citrate dihydrate and carbonate was about 11.5. Therefore, no preservatives are needed.

300 mg of ASA was placed in the dust compartment of the device.

After releasing the ASA into the test solution by cutting the seal separating the powder and solution, the device was shaken for approximately 30 seconds.

All the ASA dissolved within 10 seconds, and the pH of this obtained mixed solution was about 7.1-7.2.

Claims (11)

1. A two-component composition for use in the treatment of impending myocardial infarction, wherein the two-component composition comprises a first and a second component, wherein said first component comprises 100-600 mg of acetylsalicylic acid (ASA ) and optionally one or more pharmaceutically acceptable excipients; and wherein said second component comprises an aqueous solution comprising at least one pharmaceutically acceptable salt of an organic acid and optionally one or more pharmaceutically acceptable excipients, wherein the organic acid is selected from the group consisting of acetic acid, lactic acid, citric acid, ascorbic acid, malonic acid, succinic acid, glutaric acid and a combination thereof; and wherein the pH of the aqueous solution of the second component is 8-11.5; and wherein the pH of the solution obtained after adding and dissolving the ASA in the aqueous solution is in the range of 5-8. 2. A two-component composition for use according to claim 1, wherein the second component is an aqueous solution of a salt of citric acid, such as sodium citrate or potassium citrate. 3. A two component composition for use according to any preceding claim, wherein the second component is an aqueous solution of a salt of citric acid and a carbonate. 4. A two-component composition for use according to any preceding claim, wherein the volume of the aqueous solution of the second component is in the range 6 ml - 50 ml. 5. A two component composition for use according to claim 4, wherein the volume of the second component is in the range 8-15 ml. 6. A two-component composition for use according to claim 2 or 3, wherein the amount of aspirin in the first component is in the range of 300 to 325 mg, and the volume of the second component is in the range from 8 to 15 ml. 7. A capsule for use in the treatment of impending myocardial infarction comprising a first and a second chamber, wherein the first chamber comprises 100-600 mg of aspirin and optionally one or more pharmaceutically acceptable excipients; and wherein said second chamber comprises an aqueous solution comprising at least one pharmaceutically acceptable salt of an organic acid and optionally one or more pharmaceutically acceptable excipients, wherein the salt of an organic acid is selected from the group consisting of a salt of acetic acid, a salt of citric acid, a salt of ascorbic acid, and a combination thereof; and wherein the pH of the aqueous solution in the second chamber is 8-11.5; and wherein the pH of the solution obtained after adding and dissolving the ASA in the aqueous solution should be in the range of 5-8. 8. A capsule for use according to claim 7, wherein the second chamber comprises an aqueous solution of a salt of citric acid, such as sodium citrate or sodium citrate dihydrate. 9. A capsule for use according to any of the preceding claims 7-8, wherein the second chamber comprises an aqueous solution of a salt of citric acid and a carbonate. 10. A two-component composition for use according to claims 1-6 or a capsule for use according to claims 7-9, wherein an aqueous solution of aspirin is provided by: a) providing a two-component composition according to any of claims 1-6 or a capsule according to any of claims 7-9; b) mixing the first component or said composition or the chamber comprising a pharmaceutically acceptable amount of acetylsalicylic acid with the aqueous solution of an organic acid comprised in the second component/chamber to obtain an aqueous solution of acetylsalicylic acid. 11. A two-component composition or capsule for use according to claim 11, wherein the aqueous solution of aspirin is obtained within about two minutes or less, such as within one minute or less.